Nitric Oxide (NO) is a pervasive and physiologically active molecule in mammalian systems, and has recently been detected in the exhaled breath of humans. The concentration of NO in the exhaled breath depends on many factors including exercise, airstream flow rate, breathhold, and the presence of inflammatory diseases. It is likely that endogenously produced NO has important physiological roles in the lungs related to host defense, maintenance of bronchial smooth muscle tone, and the vascular tone of the bronchial and pulmonary circulations. Not surprisingly, inhaled exogenous NO holds promise as a therapy for diseases such as bronchial asthma, pulmonary hypertension, and Adult Respiratory Distress Syndrome (ARDS). A gas inhalation strategy can overcome many of the problems associated with intravenous or aerosol administration of drugs. In addition, the exhaled endogenous NO profile might be an extremely useful index of pulmonary inflammation and disease status. Historically, our understanding of pulmonary gas exchange dynamics has been achieved through the synergistic combination of theory and experimentation. However, current knowledge of NO exchange dynamics in the lungs has been dominated by experimentation alone. The use of modeling is particularly relevant to understanding NO exchange dynamics as many inflammatory diseases afflict the smaller airways (bronchioles) and alveoli which are essentially inaccessible to direct experimental measurement. Three hypotheses are proposed: 1) exhaled NO is derived, in part, from the respiratory region of the lungs, 2) exhaled NO is derived, in part, from the airway region of the lungs, and 3) regional heterogeneity in production, consumption, and airstream flow patterns impact exhaled concentrations. These hypotheses will be addressed by completing a series of specific aims that focus on the effect of inspiratory conditions such as flow rate, concentration, temperature, and humidity. The project will capitalize on the existing structure of a model co-developed by the PI and his lab that simulates the simultaneous exchange of heat, water, and an inert gas. The experimental results combined with the predictions of the validated model will provide the foundation for understanding the cardinal features of NO exchange dynamics in the lungs. In doing so, our understanding of lung function in health and disease will be enhanced, as well as the practical pursuit of using endogenous NO levels and exogenous NO in the clinical setting.